- In recent years, significant progress has been achieved in the understanding of the morphogenic aspects of hair follicle biology, nevertheless, the cellular, molecular and genetic aspects of hair growth control remain largely unknown, Our previous studies implicate the mouse hairless (hr) gene as a key factor in coordinating basic cellular processes during hair follicle catagen, including club hair formation, maintenance of dermal papilla-epithelial integrity, inner root sheath disintegration, and particularly, keratinocyte apoptosis in the hair matrix cells. In the hair follicle, hairless appears to function in the cellular transition to the first adult hair cycle. In its absence, in hairless (hr/hr) or rhino (rh/rh) mice, hair growth completely ceases, a new hair is never induced, and the result is a complete form of inherited atrichia. We have established that the disorder papular atrichia represents the human counterpart of the hairless and rhino mouse phenotypes, resulting from mutations in the hairless gene. However, at the molecular and cellular level, the mechanism(s) of function of the hairless protein remains largely unknown. Hairless is a single zinc-finger protein which is thought to function as a putative transcription factor. We have recently shown unequivocally that hairless is localized to the nucleus, and interestingly, that it is associated with the nuclear matrix. Protein analysis software has identified three LXXLL motifs, known as NR (nuclear receptor) boxes, which are signatures of the transcriptional coactivator family of proteins. We have compiled several lines of new evidence which implicate hairless in a pathway of genes regulated by the vitamin D receptor (VDR). These include the clinical and histological similarities between hairless mice and both VDR and retinoid X receptor (RXRa) null mice. In addition, we provide evidence that the human papular atrichia is clinically and histologically indistinguishable from vitamin D dependent rickets, with mutations in the VDR. Finally, we have identified a putative target pathway for hairless regulation which involves the upregulation of ornithine decarboxylase. We have combined our preliminary studies with several emerging lines of biological data to formulate a hypothesis which asks three questions. First, is hairless a DNA-binding protein, and if yes, what is its signature sequence? Secondly, is hairless a transcriptional coactivator, and if yes, what are its interaction partners? Finally, what are the downstream targets of hairless gene regulation? We anticipate that this approach will allow us to gain novel insights into the function of the hairless protein for the first time.